One of the greatest obstacles in developing effective treatment for injuries and degenerative diseases of the nervous system is the poor regenerative capacity of neuronal cells. Regeneration of neuronal cells in the central nervous system is currently not possible, and although neuronal cells in the peripheral nervous system show some regenerative capacity, this occurs very slowly across limited nerve gaps. Thus, individuals who experience reduction in neuronal function following injury or diseases of the central nervous system typically see little or no improvement in their condition over time, while individuals experiencing reduction in neuronal function following injury or disease of the peripheral nervous system may experience some improvement, but only after a considerable period of time. Accordingly, there exists a need for improved methods and compositions to promote neuronal regeneration in the central and peripheral nervous systems.
Neurons have cellular processes called axons that migrate and establish connections with their targets. One of the results of damage to the nervous system is the formation of glial scar tissue. Glial scar tissue is composed of astrocytes, oligodendrocytes and microglia, as well as a rich meshwork of extracellular matrix proteins including proteoglycans. Glial scar tissue formed in response to cellular damage presents a physical and/or a molecular barrier to regeneration. The content of glial scar tissue is complex, and thus the inhibitory effects of glial scar tissue may be due to multiple components of the scar. Proteoglycans are molecules consisting of one or more glycosaminoglycan (GAG) chains attached to a core protein. For example, it has been demonstrated that chondroitin sulfate proteoglycans (CSPGs) and chondroitin sulfate glycosaminoglycans (CS-GAGs), which are found in the glial scar, are inhibitory to regenerating neurons (reviewed in Silver (1994) J Neurol. 242: S22-4; Yu and Bellamkonda (2001) J. Neurosci. Res. 66: 303-310). These studies indicate that chondroitin sulfate GAGs play a role in the inhibitory effects of glial scar tissue, and additional studies suggest that the protein core of CSPGs may also play a role in inhibiting regeneration (Margolis and Margolis (1997) Cell Tissue Res. 290: 343-8; Friedlander et al. (1994) J. Cell Biol. 125: 669-680).
In addition to the inhibitory effects on regeneration mediated by glial scarring, a number of other factors may influence the rate and extent of regeneration in both the central nervous system and the peripheral nervous system. For example, inflammation is a common cellular response to trauma including trauma caused by physical injury, chemical assault, disease, and the like. Furthermore, the ability of cells to respond to local cues may be inhibited either transiently or permanently following trauma. Cells can literally be shocked by injury or disease, and thus be unable to respond to local cues including cues which may facilitate regeneration following injury.
Regardless of the mechanism underlying inhibition of neuronal regeneration following injury and disease, there exists a need to develop methods and compositions to promote regeneration. The present invention provides such methods and compositions. Given that there currently exists no effective method of promoting neuronal regeneration, the present invention addresses a crucial and currently unmet need.